The differentiation states of cancer cells influence their malignant properties. Carcinoma cells lie along a continuum of less- and more-differentiated states. At one end of this continuum reside cancer cells that retain cell-to-cell adhesion contacts and express most epithelial markers. At the other end reside stem-like cells that have lost many epithelial markers; such cells frequently upregulate mesenchymal markers (e.g., VIM, SMA, FN1), and are said to have undergone an epithelial-to-mesenchymal transition (EMT).
Less differentiated cancers generally tend to be more malignant. This basic notion is reflected in the concept of tumor grade, which is a quantitative measure of cancer cell dedifferentiation. Low-grade tumors have differentiated cancer cells; they also have a better prognosis than high-grade tumors. This critical insight serves as the foundation of tumor pathology and prognosis. Differentiation-state distinctions do not only occur between tumors, but also between the cells of a single tumor.
When taken from the same tumor, cancer cells in distinct states can have very different functional properties. For instance, in comparison to other cells in the same tumor, cancer stem-like cells (CSCs) efficiently seed new tumors, invade host tissues, and survive without cell-to-cell or cell-to-matrix attachments. In breast epithelium, experimental induction of EMT is sufficient to generate normal and cancerous stem-like cells. This indicates that carcinoma cells can acquire most metastatic traits by modulating their differentiation state.
In clinical settings, metastatic ability alone is insufficient for tumor dissemination; cancer cells must also evade therapy. Two general patterns of resistance are commonly observed: acquired resistance occurs when cancers respond initially to therapy but then develop resistance over time; intrinsic resistance occurs when cancers fail to respond initially to therapy. Remarkably, in addition to having the metastatic traits described above, CSCs also exhibit intrinsic resistance to most therapies. Several mechanisms have been proposed for how CSCs and cancer cells following EMT evade therapy, including activation of PI3K, NFκB and EGFR signaling. However, basis for intrinsic therapeutic resistance and invasiveness of certain CSCs remains minimally understood.